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O1‐04–03: Abeta reduction mechanisms by non‐viral Abeta DNA vaccination against Alzheimer's disease
Author(s) -
Matsumoto Yoh
Publication year - 2008
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2008.05.240
Subject(s) - microglia , western blot , hippocampus , vaccination , alzheimer's disease , immunology , medicine , pathology , microbiology and biotechnology , chemistry , biology , disease , inflammation , gene , biochemistry
anan et al, JPET, 2007), injected systemically (Sankaranarayanan et al, ICAD, Madrid 2006) or infused intravenously into rhesus monkeys (Simon et al, Salzburg AD/PD 2007). Methods: We have further optimized various amyloid-reducing BACE inhibitors and now report oral BACE inhibition in a unique, chronically implanted non-human primate model (Cook et al, submitted). The compound utilized in the present study has an enzymatic IC50 of 0.4 nM and cell culture IC50 of 40 nM, and PK properties suitable for in vivo use. Results: In CSF and plasma samples collected from N 8 conscious rhesus monkeys treated over a three and one-half day period in a cross-over study design, we observed a significant AUC reduction in CSF A 40 (42 %, p 0.001) and CSF A 42 (43 %, p 0.002). As anticipated from our previous rhesus infusion studies, CSF sAPP levels significantly decreased (41 %, p 0.0002), while sAPP levels trended upwards (not significant). In the periphery, plasma A 40 was dramatically reduced (61 %, p 0.005). BACE inhibition in the monkey exhibits good correlation between sAPP and CSF A 42 (r 0.78, p 0.0001) as well as between CSF A 42 and A 40 (r 0.94, p 0.0001), while CSF A 40 to Plasma A 40 shows increased scatter and variability (r 0.42, p 0.0001). Conclusions: These results are the first reported demonstration of in vivo pharmacological evidence in primates that acute brain A lowering can be achieved after oral administration of a BACE inhibitor.